• Title, Summary, Keyword: Ciliogenesis

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An Immuno-Electron Microscopic Study of Expression of $\alpha$-tubulin on Ciliogenesis in Newborn Rat Trachea (신생 횐쥐의 기관섬모에서 $\alpha$-tubulin의 발현과 섬모형성 양상에 대한 면역전자현미경적 연구)

  • 김보형;진정언;임대준;김동욱;이근수;강성호
    • Korean Journal of Bronchoesophagology
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    • v.5 no.1
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    • pp.42-48
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    • 1999
  • Background: This study was undertaken to detect the patterns of ciliogenesis in newborn rats trachea. Materials and Methods: The experimental animals(Sprague-Dawley strain) were divided five groups, one day, two day, three day, five day and seven day newborns as experimental groups. To obtain differential distribution of $\alpha$-tubulins in the ciliated cells and patterns of ciliogenesis, we used immunohistochemical stain method with mouse anti $\alpha$-tubulin monoclonal antibody as the primary antibody and gold particles conjugated goat anti mouse IgG as the secondary antibody. And we observed the specimens by electron microscope (Hitach-600 Model). Results : 1) The distribution of the $\alpha$ -tubulin reactions in apical zone was slightly decreased from three day after birth. 2) From 5th day after birth, the decreasing number of gold particles in intermediate zone was remarkable. 3) On the comparison with the other zones, the number of gold particles in the Golgi zone for seven days showed no statistical difference. Conclusion : The ciliogenesis of the tracheal ciliated cells in early newborn rat were made via centriolar and acentriolar pathways, in late groups, from five day after birth, the major ciliogenesis pattern might be centriolar pathway.

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Deficiency of calpain-6 inhibits primary ciliogenesis

  • Kim, Bo Hye;Kim, Do Yeon;Oh, Sumin;Ko, Je Yeong;Rah, Gyuyeong;Yoo, Kyung Hyun;Park, Jong Hoon
    • BMB Reports
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    • v.52 no.10
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    • pp.619-624
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    • 2019
  • The primary cilium is a microtubule-based structure projecting from a cell. Although the primary cilium shows no motility, it can recognize environmental stimuli. Thus, ciliary defects cause severe abnormalities called ciliopathies. Ciliogenesis is a very complex process and involves a myriad of components and regulators. In order to excavate the novel positive regulators of ciliogenesis, we performed mRNA microarray using starved NIH/3T3 cells. We selected 62 murine genes with corresponding human orthologs, with significantly upregulated expression at 24 h after serum withdrawal. Finally, calpain-6 was selected as a positive regulator of ciliogenesis. We found that calpain-6 deficiency reduced the percentage of ciliated cells and impaired sonic hedgehog signaling. It has been speculated that this defect might be associated with decreased levels of ${\alpha}-tubulin$ acetylation at lysine 40. This is the first study to report a novel role of calpain-6 in the formation of primary cilia.

Cell cycle-related kinase is a crucial regulator for ciliogenesis and Hedgehog signaling in embryonic mouse lung development

  • Lee, Hankyu;Ko, Hyuk Wan
    • BMB Reports
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    • v.53 no.7
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    • pp.367-372
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    • 2020
  • Cell cycle-related kinase (CCRK) has a conserved role in ciliogenesis, and Ccrk defects in mice lead to developmental defects, including exencephaly, preaxial polydactyly, skeletal abnormalities, retinal degeneration, and polycystic kidney. Here, we found that Ccrk is highly expressed in mouse trachea and bronchioles. Ccrk mutants exhibited pulmonary hypoplasia and abnormal branching morphogenesis in respiratory organ development. Furthermore, we demonstrated that Ccrk mutant lungs exhibit not only impaired branching morphogenesis but also a significant sacculation deficiency in alveoli associated with reduced epithelial progenitor cell proliferation. In pseudoglandular stages, Ccrk mutant lungs showed a downregulation of Hedgehog (Hh) signaling and defects in cilia morphology and frequency during progenitor-cell proliferation. Interestingly, we observed that activation of the Hh signaling pathway by small-molecule smoothened agonist (SAG) partially rescued bud morphology during branch bifurcation in explants from Ccrk mutant lungs. Therefore, CCRK properly regulates respiratory airway architecture in part through Hh-signal transduction and ciliogenesis.

Primary Cilia, A Novel Bio-target to Regulate Skin Pigmentation (바이오 안테나인 일차 섬모 조절을 통한 피부 미백 기술)

  • Choi, Hyunjung;Park, Nokhyun;Kim, Jihyun;Cho, Dong-Hyung;Lee, Tae Ryong;Kim, Hyoung-June
    • Journal of the Society of Cosmetic Scientists of Korea
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    • v.44 no.1
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    • pp.73-79
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    • 2018
  • The primary cilium protrudes from the cell body like a bio-antenna that has many receptors, channels and signaling molecules to sense and response to external stimuli. The external environment such as ultraviolet irradiation, temperature, humidity, gravity and shear stress always influences skin. Skin responds to external stimuli and differentiates by making melanin, collagen and horny layer. Ciliogenesis participates in developmental processes of skin, such as keratinocyte differentiation and hair formation. And it was reported that skin pigmentation was inhibited when ciliogenesis was induced by sonic hedgehog-smoothened-GLI2 signaling. When skin is exposed to ultraviolet irradiation, alpha-melanocyte stimulating hormones (${\alpha}$-MSH) increase melanin synthesis through activation of the cAMP pathway in melanocytes. We observed that ${\alpha}$-MSH and cAMP production inducers inhibited ciliogenesis of melanocytes. Therefore, we thought that regulation of ciliogenesis is potential candidate target for the development of agents to treat undesirable hyperpigmentation of skin. As a result, we found out that an ethanol extract of Glycyrrhiza glabra (EGG) root and 3,4,5-trimethoxy cinnamate thymol ester (TCTE, Melasolv) significantly inhibit melanin synthesis of normal human melanocyte by inducing primary cilium formation. This study proposed new theory to regulate skin pigmentation and cosmetic components for skin whitening.

The primary cilium as a multiple cellular signaling scaffold in development and disease

  • Ko, Hyuk-Wan
    • BMB Reports
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    • v.45 no.8
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    • pp.427-432
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    • 2012
  • Primary cilia, single hair-like appendage on the surface of the most mammalian cells, were once considered to be vestigial cellular organelles for a past century because of their tiny structure and unknown function. Although they lack ancestral motility function of cilia or flagella, they share common ground with multiciliated motile cilia and flagella on internal structure such as microtubule based nine outer doublets nucleated from the base of mother centrioles called basal body. Making cilia, ciliogenesis, in cells depends on the cell cycle stage due to reuse of centrioles for cell division forming mitotic spindle pole (M phase) and assembling cilia from basal body (starting G1 phase and maintaining most of interphase). Ciliary assembly required two conflicting processes such as assembly and disassembly and balance between these two processes determines the length of cilia. Both process required highly conserved transport system to supply needed substance to grow tip of cilia and bring ciliary turnover product back to the base of cilia using motor protein, kinesin and dynein, and transport protein complex, IFT particles. Disruption of ciliary structure or function causes multiple human disorder called ciliopathies affecting disease of diverse ciliated tissues ranging from eye, kidney, respiratory tract and brain. Recent explosion of research on the primary cilia and their involvement on animal development and disease attracts scientific interest on how extensively the function of cilia related to specific cell physiology and signaling pathway. In this review, I introduce general features of primary cilia and recent progress in understanding of the ciliary length control and signaling pathways transduced through primary cilia in vertebrates.

Repeated restraint stress promotes hippocampal neuronal cell ciliogenesis and proliferation in mice

  • Lee, Kyounghye;Ko, Hyuk Wan
    • Laboraroty Animal Research
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    • v.34 no.4
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    • pp.203-210
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    • 2018
  • Stress severely disturbs physiological and mental homeostasis which includes adult neurogenesis in hippocampus. Neurogenesis in hippocampus is a key feature to adapt to environmental changes and highly regulated by multiple cellular signaling pathways. The primary cilium is a cellular organelle, which acts as a signaling center during development and neurogenesis in adult mice. However, it is not clear how the primary cilia are involved in the process of restraint (RST) stress response. Using a mouse model, we examined the role of primary cilia in repeated and acute RST stress response. Interestingly, RST stress increased the number of ciliated cells in the adult hippocampal dentate gyrus (DG). In our RST model, cell proliferation in the DG also increased in a time-dependent manner. Moreover, the analysis of ciliated cells in the hippocampal DG with cell type markers indicated that cells that were ciliated in response to acute RST stress are neurons. Taken together, these findings suggest that RST stress response is closely associated with an increase in the number of ciliated neurons and leads to an increase in cell proliferation.

Ciliary subcompartments: how are they established and what are their functions?

  • Lee, Jeongmi;Chung, Yun Doo
    • BMB Reports
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    • v.48 no.7
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    • pp.380-387
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    • 2015
  • Cilia are conserved subcellular organelles with diverse sensory and developmental roles. Recently, they have emerged as crucial organelles whose dysfunction causes a wide spectrum of disorders called ciliopathies. Recent studies on the pathological mechanisms underlying ciliopathies showed that the ciliary compartment is further divided into subdomains with specific roles in the biogenesis, maintenance and function of cilia. Several conserved sets of molecules that play specific roles in each subcompartment have been discovered. Here we review recent progress on our understanding of ciliary subcompartments, especially focusing on the molecules required for their structure and/or function. [BMB Reports 2015; 48(7): 380-387]

Ectopic Expression of Cenexin1 S796A Mutant in $ODF2^{+/-}$ Knockout Background Causes a Sperm Tail Development Defect

  • Lee, Kyung Ho
    • Development and Reproduction
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    • v.16 no.4
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    • pp.363-370
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    • 2012
  • The outer dense fiber 2 (ODF2) protein is an important component of sperm tail outer dense fiber and localizes at the centrosome. It has been reported that the RO072 ES cell derived homozygote knock out of ODF2 results in an embryonic lethal phenotype, and XL169 ES cell derived heterozygote knock out causes severe defects in sperm tail development. The ODF2s splicing variant, Cenexin1, possesses a C-terminal extension, and the phosphorylation of serine 796 residue in an extended C-terminal is responsible for Plk1 binding. Cenexin1 assembles ninein and causes ciliogenesis in early stages of the cell cycle in a Plk1-independent manner. Alternatively, in the late stages of the cell cycle, G2/M phase, Cenexin1 binds to Plk1 and results in proper mitotic progression. In this study, to identify the in vivo function of Plk1 binding to phosphorylated Cenexin1 S796 residue, and to understand the in vivo functional differences between ODF2 and Cenexin1, we generated ODF2/Cenexin1 S796A/Cenexin1 WT expressing transgenic mice in a RO072 ES cell derived $ODF2^{+/-}$ knock out background. We observed a severe defect of sperm tail development by ectopic expression of Cenexin1 S796A mutant and no phenotypic differences between the ectopic expression of ODF2/Cenexin1 WT in $ODF2^{+/-}$ background and in normal wild type mice.

Autophagy Regulates Formation of Primary Cilia in Mefloquine-Treated Cells

  • Shin, Ji Hyun;Bae, Dong-Jun;Kim, Eun Sung;Kim, Han Byeol;Park, So Jung;Jo, Yoon Kyung;Jo, Doo Sin;Jo, Dong-Gyu;Kim, Sang-Yeob;Cho, Dong-Hyung
    • Biomolecules & Therapeutics
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    • v.23 no.4
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    • pp.327-332
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    • 2015
  • Primary cilia have critical roles in coordinating multiple cellular signaling pathways. Dysregulation of primary cilia is implicated in various ciliopathies. To identify specific regulators of autophagy, we screened chemical libraries and identified mefloquine, an anti-malaria medicine, as a potent regulator of primary cilia in human retinal pigmented epithelial (RPE) cells. Not only ciliated cells but also primary cilium length was increased in mefloquine-treated RPE cells. Treatment with mefloquine strongly induced the elongation of primary cilia by blocking disassembly of primary cilium. In addition, we found that autophagy was increased in mefloquine-treated cells by enhancing autophagic flux. Both chemical and genetic inhibition of autophagy suppressed ciliogenesis in mefloquine-treated RPE cells. Taken together, these results suggest that autophagy induced by mefloquine positively regulates the elongation of primary cilia in RPE cells.

Primary cilia in energy balance signaling and metabolic disorder

  • Lee, Hankyu;Song, Jieun;Jung, Joo Hyun;Ko, Hyuk Wan
    • BMB Reports
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    • v.48 no.12
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    • pp.647-654
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    • 2015
  • Energy homeostasis in our body system is maintained by balancing the intake and expenditure of energy. Excessive accumulation of fat by disrupting the balance system causes overweight and obesity, which are increasingly becoming global health concerns. Understanding the pathogenesis of obesity focused on studying the genes related to familial types of obesity. Recently, a rare human genetic disorder, ciliopathy, links the role for genes regulating structure and function of a cellular organelle, the primary cilium, to metabolic disorder, obesity and type II diabetes. Primary cilia are microtubule based hair-like membranous structures, lacking motility and functions such as sensing the environmental cues, and transducing extracellular signals within the cells. Interestingly, the subclass of ciliopathies, such as Bardet-Biedle and Alström syndrome, manifest obesity and type II diabetes in human and mouse model systems. Moreover, studies on genetic mouse model system indicate that more ciliary genes affect energy homeostasis through multiple regulatory steps such as central and peripheral actions of leptin and insulin. In this review, we discuss the latest findings in primary cilia and metabolic disorders, and propose the possible interaction between primary cilia and the leptin and insulin signal pathways which might enhance our understanding of the unambiguous link of a cell's antenna to obesity and type II diabetes.